Neoadjuvant SBRT followed by evorpacept and pembrolizumab in HPV-mediated head and neck squamous cell carcinoma: Investigation of pathologic response.

Abstract

e18101 Background: Recent attempts to de-escalate nonsurgical treatment for HPV mediated (HPV+) head and neck squamous cell carcinoma (HNSCC) have not been successful and current treatment regimens of concurrent chemotherapy and radiation with comprehensive elective nodal irradiation still incur significant long-term morbidity. Prior studies have shown that a neoadjuvant approach of tumor focused, lymphatic sparing stereotactic body radiation therapy (SBRT) with anti-PD-1/PD-L1 in patients with both HPV+ and HPV unrelated HNSCC is safe and results in a high rate of pathologic response. Based on these data and evidence showing that dendritic cell migration and activation are key to immunoradiotherapy responses, we are conducting a phase II trial of neoadjuvant SBRT followed by combination evorpacept/pembrolizumab in HPV+ HNSCC with the goal of reducing long term toxicity while achieving similar or better oncologic outcomes compared to historical controls. Methods: Patients with resectable cT0-2N1M0 Stage I HPV+ oropharynx cancer (not eligible for surgery alone, i.e. multiple nodes or solitary node >3 cm) are treated with 8 Gy x 3 neoadjuvant SBRT (GTV + 3 mm) followed by 2 cycles of combination evorpacept + pembrolizumab, followed by transoral primary tumor resection with neck dissection and by risk adapted adjuvant radiation or chemoradiation if indicated. The primary endpoint is pathologic complete response (pCR). A Simon-two stage design will test a non-inferiority goal against standard of care (i.e. pCR at surgery < 70% vs >80%, n=27 patients). Secondary endpoints include MPR, safety, survival, and pathologic down-staging allowing for omission of adjuvant therapy. Results: To date an interim futility analysis has been completed and evaluated, with pCR in 6/6 (100%) of patients, no surgical complications, no recurrences, and no additional adjuvant radiation or chemotherapy needed in any patient. Patients had excellent functional swallowing outcomes after neoadjuvant therapy and at the conclusion of treatment after surgery. Treatment toxicities were primarily related to combinatorial immunotherapy, with 2/6 patients with grade III or IV toxicity (hepatitis and pancytopenia respectively) rapidly reversible with steroid therapy prior to surgery. Conclusions: This trial of neoadjuvant SBRT followed by evorpacept and pembrolizumab in HPV+ HNSCC has fulfilled an interim futility analysis with pCR in all patients, and an acceptable rate of reversible grade III or greater toxicity related to systemic immunotherapy. Further enrollment will proceed to define primary pCR endpoints and secondary functional and oncologic endpoints. Clinical trial information: NCT05787639 .